The overall goal of the City of Hope Lymphoma SPORE is to develop novel therapeutics and prognostics representing the forefront of knowledge gained from observations in molecular biology and cellular immunology at City of Hope. Six clinical trials are proposed, five of which utilize agents (cellular products, small molecules, radiolabeled antibodies) that have been produced at City of Hope and are developed from our preclinical laboratory studies. In Project 1, we have engineered bi-specific chimeric antigen receptor (CAR) T cells that respond to both lymphoma antigen and cytomegalovirus (CMV) antigen. Combining bi-specific CAR T cells with a CMV vaccine developed at City of Hope may enhance CAR T cell persistence and allow in vivo control of T cells in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) in three clinical settings: 1) lymphodepleting chemotherapy, 2) autologous (auto) hematopoietic cell transplantation (HCT), and 3) allogeneic HCT. Project 2 builds on our previous observations in a prospective longitudinal study of lymphoma patients undergoing auto HCT, revealing pathogenic mutations contributing to a predictive 38-gene signature of susceptibility to tMDS/AML. We will now use this City of Hope cohort and an external validation cohort to develop a comprehensive risk prediction model for developing t-MDS/AML after auto HCT. Project 3 addresses the poor outcomes for patients with relapsed Hodgkin lymphoma with two phase II clinical trials: a PET-adapted strategy using PD-1 inhibitor nivolumab ICE chemotherapy as a bridge to autologous HCT, and aTac-BEAM, a radioimmunotherapy-based augmented autologous HCT regimen. In Project 4, we propose a clinical trial of a novel agent linking a CpG oligonucleotide with anti-sense STAT3 siRNA to target NHL and associated immune cells. We are also developing a modified high-affinity STAT3-DNA binding sequence linked to a CpG oligonucleotide that inhibits STAT3 by acting as DNA decoy. The SPORE, also supports a Career Enhancement Program for researchers new to lymphoma research, as well as a Developmental Research Program for scientists with promising pilot projects. SPORE cores provide crucial support to the success of the projects: The Administrative Core (Core A) provides organizational and programmatic support; the Biostatistics and Research Informatics Core (Core B) imparts comprehensive statistical and information management expertise; and Biospecimen Core (Core C) supports projects as they relate to sample collection, processing, storage and distribution. The GMP Manufacturing Core (Core D) is responsible for process development, regulatory support, and cGMP-compliant clinical grade production of novel investigational agents; this core is an invaluable resource allowing us to rapidly translate laboratory discoveries to the clinic. Lastly, with a richly diverse catchment area, City of Hope has made a coordinated effort to engage patients that have been traditionally underrepresented and underserved in clinical trials. In sum, this SPORE holds high potential to make significant inroads in improving outcomes for lymphoma patients.